Anti-curare agents

Abstract

This invention relates to a method for antagonizing induced the neuromuscular blocking effects of certain therapeutic agents and pathological disorders in mammals, which comprises administering to said mammal an antagonizing-effective amount of a compound of the formula: ##STR1## wherein R 1 and R 2 are each hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkyl-lower alkyl or hydroxyalkyl, or, when taken together, form a heterocyclic ring with the nitrogen to which they are attached, with the proviso that both are not hydrogen; R 3 is hydrogen or alkyl; and R 4 is hydrogen, alkyl, alkenyl, alkynyl, halogen or acyl; or a salt thereof with acids.

What is claimed is: 
     
       1. A method for antagonizing neuromuscular blocking effects induced by therapeutic agents and physiological disorders in mammals, which comprises administering to said mammal an antagonizing-effective amount of a compound of the formula: ##STR5## wherein R 2  and R 2  are each hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aralkyl, cycloalkyl, cycloalkyl-lower alkyl or hydroxyalkyl, with the proviso that both are not hydrogen; R 3  is hydrogen or lower alkyl; and   R 4  is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen or acyl; wherein the alkyl groups in alkyl per se, aralkyl, cycloalkyl-lower alkyl and hydroxyalkyl contain from 1 to 6 carbon atoms; the cycloalkyl groups in cycloalkyl per se and cycloalkyl-lower alkyl contain from 4 to 8 carbon atoms; the alkenyl and alkynyl groups contain from 2 to 6 carbon atoms; the acyl group contains from 1 to 6 carbon atoms; and the aryl groups in aryl per se and aralkyl contain from 6 to 10 carbon atoms; or a salt thereof with acid.   
     
     
       2. The method according to claim 1 wherein R 1  and R 2  are each selected from the group consisting of lower alkyl, aryl, and aralkyl, R 3  and R 4  are each hydrogen.   
     
     
       3. The method according to claim 2 wherein R 1  and R 2  are each lower alkyl. 
     
     
       4. The method according to claim 2 wherein R 1  and R 2  are each methyl. 
     
     
       5. The method of claim 4 wherein the compound is 1,1-diemethyl-3-(4-amino-3-pyridyl) urea. 
     
     
       6. The method of claim 1 wherein the therapeutic agent is selected from the group consisting of a nondepolarizing muscle relaxant, an antibiotic which inhibits neuromuscular transmission and magnesium. 
     
     
       7. The method of claim 6 wherein the muscle relaxant is curare, d-tubocurarine or pancuronium. 
     
     
       8. The method of claim 6 wherein the antibiotic is an aminoglycoside, polypeptide-type antibiotic, lincomycin or spectinomycin. 
     
     
       9. The method of claim 1 wherein the disorder is botulism A. 
     
     
       10. The method of claim 1 wherein the disorder is myasthenia gravis. 
     
     
       11. The method of claim 1 wherein the disorder is Eaton-Lambert Syndrome. 
     
     
       12. The method of claim 1 wherein the disorder is senile dementia (Altzheimer's type). 
     
     
       13. The method of claim 1 wherein the disorder is multiple sclerosis. 
     
     
       14. The method of claim 6 wherein the compound is administered intravenously. 
     
     
       15. The method of claim 14 wherein the compound is administered in an amount of from about 0.1 to 2.0 mg/kg. 
     
     
       16. The method of claim 9 wherein the compound is administered by intravenous infusion of about 0.1 to 2.0 mg/ml solution. 
     
     
       17. The method of claim 10 wherein the compound is administered intravenously, orally or rectally. 
     
     
       18. The method of claim 17 wherein, when administered intravenously, the compound is administered in an amount of from about 0.1-2.0 mg/kg. 
     
     
       19. The method of claim 17 wherein, when administered orally or rectally, the compound is administered in an amount of from about 0.3 to 6.0 mg/kg. 
     
     
       20. The method of claim 11 wherein the compound is administered intravenously, orally or rectally. 
     
     
       21. The method of claim 20 wherein, when administered intravenously, the compound is administered in an amount of from about 0.1 to 2.0 mg/kg. 
     
     
       22. The method of claim 20 wherein, when administered orally or rectally, the compound is present in an amount of from about 0.3-6.0 mg/kg. 
     
     
       23. The method of claim 12 wherein the compound is administered orally. 
     
     
       24. The method of claim 23 wherein the compound is in an amount of about 0.1 to 3.0 mg/kg. 
     
     
       25. The method of claim 13 wherein the compound is administered intravenously, orally or rectally. 
     
     
       26. The method of claim 25 wherein, when administered intravenously, the compound is administered in an amount of from about 0.1 to 2.0 mg/kg. 
     
     
       27. The method of claim 25 wherein, when administered orally or rectally, the compound is administered in an amount of from about 0.3 to 6.0 mg/kg. 
     
     
       28. A therapeutic composition for the antagonism of neuromuscular block which comprises a compound of the formula: ##STR6## at a unit dosage level of from about 0.1 to about 6.0 mg/kg. wherein R 1  and R 2  are each hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aralkyl, cycloalkyl, cycloalkyl-lower alkyl or hydroxyalkyl, with the proviso that both are not hydrogen; R 3  is hydrogen or alkyl; and   R 4  is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, or halogen or acyl; wherein the alkyl groups in alkyl per se, aralkyl, cycloalkyl-lower alkyl and hydroxyalkyl contain from 1 to 6 carbon atoms; the cycloalkyl groups in cycloalkyl per se and cycloalkyl-lower alkyl contain from 4 to 8 carbon atoms; the alkenyl and alkynyl groups contain from 2 to 6 carbon atoms; the acyl group contains from 1-6 carbon atoms and the aryl groups in aryl per se and aralkyl contain from 6 to 10 carbon atoms;   or a salt thereof with acid.